Elucidating how the respiratory tract microbiota regulate immune responses to bacterial infection

慢性阻塞性肺疾病（COPD）是一种常见的肺部疾病，发生在吸烟者和非吸烟者身上。最新统计数据显示，COPD影响约8%的英国人口，该疾病现在是全球第三大死亡原因。COPD患者容易受到有害细菌的感染，导致急性症状发作（“恶化”），破坏性发作，死亡率为1/4。我们迫切需要提高我们对为什么一些患者更容易感染的理解。我们可以利用这种理解来开发治疗这种疾病的新方法，目的是改善患者的生活质量和结果。最近的研究表明，肺部有数百万的常驻“肠道”细菌（“微生物组”），这可能有助于防止其他更有害的细菌引发的感染。COPD患者在其微生物组中显示出某些细菌的生长。我们不知道这种生长是否只是疾病的结果，或者通过扰乱免疫系统，特定的细菌实际上有助于增加对有害细菌感染的易感性。该项目提出了以下三个问题：1.肺内的唾液酸在预防有害细菌感染方面是否具有一般保护作用？2. COPD中发生的微生物组的特定变化是否会降低免疫系统抵抗有害细菌感染的能力？3.我们是否可以将健康人的药物用于COPD患者，以提高他们抵抗有害细菌感染的能力？这项研究将由帝国理工学院和牛津大学的科学家合作进行，并将采取双管齐下的方法来回答这些问题。首先，将在一组COPD患者中研究肺部微生物组，以确定那些患有非常严重的有害细菌感染的患者是否会产生或减少某些细菌。这些研究将确定可能降低免疫系统对抗有害细菌能力的特定药物。然后我们将在老鼠身上进行实验，这在伦理上是不可能在人类身上进行的。我们将通过抗生素治疗实验性地消除肺部微生物组，然后重新引入在患有严重感染的COPD受试者中发现增加的抗生素。然后，我们将用有害细菌感染这些小鼠，并研究抗生素如何影响免疫系统对抗这些细菌的能力。这些实验将使我们能够回答微生物组是否会直接导致COPD感染易感性增加。最后，我们将使用模拟患者中观察到的许多微生物组变化的COPD小鼠模型，以确定“健康”药物的施用是否可以增强免疫系统对有害细菌感染的反应。预计这项工作将确定可以直接扰乱或增强免疫系统的重要药物。这将导致新疗法的开发，其中健康的抗生素可以被引入COPD患者的肺部，以增强他们在接触有害细菌时的免疫反应。总之，这项研究将为一个具有巨大临床重要性的领域提供新的科学见解，并促进开发令人兴奋的新疗法，以减轻COPD引起的疾病负担。

Chronic obstructive pulmonary disease (COPD) is a common lung disorder that occurs in both smokers and non-smokers. Latest statistics show that COPD affects ~8% of the UK population and the disease is now the 3rd leading cause of death worldwide. Patients with COPD are prone to infections by harmful bacteria that lead to acute symptom flare-ups ('exacerbations'), devastating episodes with a 1 in 4 mortality rate. We urgently need to improve our understanding of why some patients are more susceptible to infections. We could use this understanding to develop new ways of treating the condition with the aim of improving quality of life and outcomes for patients. Recent studies have revealed that the lungs are colonised by millions of resident 'commensal' bacteria (the 'microbiome') which may help to protect against infections triggered by other more harmful bacteria. COPD patients show outgrowth of certain commensals within their microbiome. We do not know whether this outgrowth is just a consequence of the disease or if, by upsetting the immune system, specific commensals actually contribute to increased susceptibility to infection by harmful bacteria.This projects asks the following three questions:1. Do commensals in the lung have a general protective role in preventing infections by harmful bacteria? 2. Do specific changes in the microbiome that occur in COPD reduce the immune system's ability to fight infection by harmful bacteria?3. Could we administer commensals from healthy people into patients with COPD to improve their ability to fight infection by harmful bacteria?This research will be carried out by collaborating scientists at Imperial College and University of Oxford and will take a two-pronged approach to answer these questions. Firstly, the lung microbiome will be studied in a group of patients with COPD to determine if those who have very severe infections by harmful bacteria have outgrowth or reduction of certain commensals. These studies will pinpoint specific commensals that may reduce the immune system's ability to fight harmful bacteria. We will then conduct experiments in mice that are not ethically possible in humans. We will experimentally abolish the lung microbiome with antibiotic treatment and then reintroduce commensals found to be increased in COPD subjects who have severe infections. We will then infect these mice with harmful bacteria and study how commensals affect the immune system's ability to fight off these bacteria. These experiments will allow us to answer whether the microbiome can directly contribute to increased infection susceptibility in COPD. Finally, we will use a mouse model of COPD which mimics many of the microbiome changes seen in patients to determine if administration of 'healthy' commensals can boost the immune system's response to a harmful bacterial infection. It is anticipated that this work will identify important commensals that can directly upset or enhance the immune system. This would then lead to development of new therapies where healthy commensals could be introduced into the lungs of patients with COPD to boost their immune response when exposed to harmful bacteria. In summary, this research will provide new scientific insight into an area of huge clinical importance and facilitate development of exciting new therapies to reduce the burden of disease caused by COPD.